Pictet with ketones

Friedel-Crafts reaction. Iodine is a mild catalyst for the Pictet-Spengler reaction of tryptamine with ketones to generate tetrahydro-P-carbolines at room temperature. ... 

Pictet-Spengler ring closure with ketones l,2,3,4-Tetrahydro-9H-pyrido[3,4-b]indoles from tryptamines... 

The first enantioselective synthesis of 5,6-dihydroindolo[l,2-a]quinox-alines (200) has been achieved by using a newly developed Hg-BINOL-lype imidodiphosphoric acid catalyst (201) in the Pictet-Spengler-type reactions of indolyl anilines (198) with ketones (199) to afford the products in high yields (up to 97%) and excellent enantioselectivities (up to 98% ee) (Scheme 53). ... 

The Pictet-Spengler reaction is one of the key methods for construction of the isoquinoline skeleton, an important heterocyclic motif found in numerous bioactive natural products. This reaction involves the condensation of a P-arylethyl amine 1 with an aldehyde, ketone, or 1,2-dicarbonyl compound 2 to give the corresponding tetrahydroisoquinoline 3. These reactions are generally catalyzed by protic or Lewis acids, although numerous thermally-mediated examples are found in the literature. Aromatic compounds containing electron-donating substituents are the most reactive substrates for this reaction. 

Reaction of tryptamine with simple ketones has not been widely explored. Acetone in the presence of benzoyl chloride has been reported to yield 2-benzoyl-1,1 -dimethyl-1,2,3,4-tetrahydro-j8-carbo-line. That the keto group is much less reactive than the aldehyde group is indicated by the fact that j8-keto aldehydes, in the form of their acetals or sodium salts, react with tryptamine at the aldehyde function to yield the conjugated enamine 24, which undergoes ring closure via an intramolecular Michael addition. The potentialities of this interesting modification of the Pictet-Spengler reaction have not yet been fuUy explored. 

The Pictet-Spengler reaction has mainly been investigated as a potential source of polycyclic heterocycles for combinatorial apphcations or in natural product synthesis [149]. Tryptophan or differently substituted tryptamines are the preferred substrates in a cyclocondensation that involves also aldehydes or activated ketones in the presence of an acid catalyst. Several versions of microwave-assisted Pictet-Spengler reactions have been reported in the hter-ature. Microwave irradiation allowed the use of mild Lewis acid catalysts such as Sc(OTf)3 in the reaction of tryptophan methyl esters 234 with different substituted aldehydes (aliphatic or aromatic) [150]. Under these conditions the reaction was carried out in a one-pot process without initial formation of the imine (Scheme 86). 

Yen and Chu subsequently also disclosed a related Pictet-Spengler reaction involving tryptophan and ketones for the preparation of 1,1-disubstituted indole alkaloids [417]. In the approach shown in Scheme 6.234, tryptophan was reacted with numerous ketones (12 equivalents) in toluene in the presence of 10 mol% of trifluoroacetic acid catalyst. Using microwave irradiation at 60 °C under open-vessel conditions, the desired products were obtained in high yields. Compared to transformations carried out at room temperature, reaction times were typically reduced from days to minutes. Subsequent treatment with isocyanates or isothiocyanates led to tetrahydro-/8-carbolinehydantoins. 

The pyrrolo[3, 4 2,3]azepino[4,5,6-cd] indole-8,10-dione system can be accessed by reaction, under conditions used for the Pictet-Spengler reaction, of the imines from condensation of 3-amino-4-(3-indolyl) pyrrolin-2,5-diones with aldehydes or ketones. Cyclisation to the pyrrolo-P-carbolines did not occur under the conditions <00JHC1177>. 

On the basis of data obtained in the previous paragraphs, one can propose that formation of 5-oxoniachrysenes 67 (R2 = H) occurs via the primary O-formylation of 66 followed by cyclization of esters 70 (R2 = R3 = H), which is similar to the Pictet-Gams reaction (80T1279). Obviously, this mechanism can also be applied to the acylation of 66 with R2COOH (R2 does not equal H) in PPA in contrast to the scheme of formation of 2-benzopyrylium cations 30 from benzyl ketones 28 (Section II, C, 2). 

An alternative synthesis of ( )-a- and ( )--y-lycoranes (57 and 93) commenced with the 2-oxocyclohexyl acetic acid derivative 114 obtained by the alkylation of the enamine derived from 113 (Scheme 10) (116). Refluxing the oxime of 114 with zinc dust in glacial acetic acid afforded a mixture of the lactams 115, 116, and 117 in an approximate ratio of 4 6 3. The structure of 115 was verified by catalytic hydrogenation to give the lactam 118, which had previously been converted to ( )-a-lycorane (57). When the lactam 116 was subjected to sequential catalytic hydrogenation, hydride reduction, and Pictet-Spengler cyclization, ( )-y-lycorane (93) was obtained. A more efficient route to ( )-a-lycorane (57) involved refluxing the ketone 114 first with benzylamine in xylene and then with 87% formic acid to furnish the unsaturated lactam 119. 

Silveira, C. C. Bemardi, C. R. Braga, A. L. Kaufman, T. S. Elaboration of 1-benzoyltetra-hydroisoquinoline derivatives employing a Pictet-Spengler cyclization with a-chloro a-phenylthio ketones. Synthesis of O-methyl-velucryptine. Tetrahedron Lett. 2001, 42, 8947-8950. 

Scheme 36 Pictet-Spengler reaction of tryptophan with various ketones...

Scheme 1.6f). Reaction of the -allylie alcohol 12 with formaldehyde in the presence of acid catalyst and sodium sulfate gave the oxazolidine 13. Exposure of 13 to 2.4 equivalents of BF3 OEt2 provided a key intermediate hydroindolone (14) in 97% yield as a single diastereomer. Hydrogenolysis of 14 followed by Pictet-Spengler cyclization afforded the methanomorphanthridine ketone 15 in 65% yield. 

Excellent yields of isochromans are obtained when 2-phenylethanol derivatives react with aldehydes and, with lower yields, ketones in the presence of the zeolite Ersorb-4a. This variation of the oxa-Pictet-Spengler reaction is simple, cheap and environmentally-ffiendly <060BC1220>. 

Asymmetric induction in ring closure reactions of central chiral ferrocene derivatives has been reported. Moderate diastereoselectivity was found in the ring closure of the enantiomeric 4-ferrocenyl-2-methyl-2-phenyl-butanoic acids by treatment with trifluoroacetic anhydride (Fig. 4-211) [10]. The diastereoisomeric ketones could be separated by chromatography. A higher induction was observed in an asymmetric Pictet — Spengler type cyclization of a reactive imine formed from enantiomerically pure 2-ferrocenyl-2-propylamine and formaldehyde, as only one isomer of the product was detected (Fig. 4-21 g) [135, 136]. 

The research group of S.J. Danishefsky investigated model systems in an effort directed toward the total synthesis of ET 743 and its analogues. The stereoselective formation of the spiro stereocenter of the ABFGH subunit of ET 743 was installed via a Pictet-Spengler reaction. The electron-rich phenylethylamine was mixed with a slight excess of the ketone substrate and the cyclization took place at room temperature in the presence of silica gel. 

First described by Kaljuste and Unden [34], the reaction of polymer-bound tryptophan with a variety of aldehydes and ketones under Pictet-Spengler conditions [35] has also been reported by Mayer et al. [36]. The j8-carboline derivatives 5 exhibited significant bioactivity. Following incorporation of 9-fluorenylmethoxycarbonyl (Fmoc)-tryptophan and deprotection, the condensation with an aldehyde or ketone under acidic conditions provided the /3-carbolines in high yield and purity. The same strategy has been published... 

More recently, Chu and coworkers prepared diastereoisomers of 1,3-disubstituted l,2,3,4-tetrahydro-j5-carbolines in short times (0.5 to 4 h) with good yields (50-98%) using the Pictet-Spengler reactions of tryptophan with aldehydes under acidic conditions at ambient temperature [124]. Although reaction rates are intrinsically slow, ketone reactions can be accelerated (from days to minutes) by using microwaves with open vessels isolated yields are high (67-99%). 

Some biosynthetic studies involving incorporation of labelled tyrosine, cysteine, methionine, glycine and tryptophane [68,69], have already been performed on the ecteinascidins, to partially confirm the proposed biosynthetic origin of the A and B units from Dopa units. Further studies are in progress to test the hypothesis that the electrophilic ketone in an intermediate such as Et 594 or Et 596 can be condensed in a Pictet-Spengler reaction with a Dopa derivative to form the third tetrahydroisoquinoline group (C unit) in Et 729 or Et 743 [68]. 

Pictet and Gams (51) carried out the first complete synthesis of the alkaloid in 1909. Veratrol was acetylated in a Friedel-Crafts reaction, the acetoveratrone (XXX) was treated with nitrous acid, and the corresponding isonitroso derivative reduced to aminoacetoveratrone (XXXI) with tin and hydrochloric acid. The hydrochloride of this a-amino ketone was condensed with homoveratroyl chloride, and the resulting homovera-... 

We also considered preparation of the dihydro analogues via Pictet-Spengler cychzation (i.e., cyclization with a unit of formaldehyde). However, if the cyclizations were successful, subsequent oxidations would be required to accomplish the aromatization. Unfortunately, under all conditions screened, the Pictet-Spengler cyclization was not effective on C3-ketones. Modification of the electronics by variation of the substituents on both the pyrrole nitrogen and the C6-nitrogen also failed to give productive cyclization. 

Although the Skraup/Doebner-von Miller reaction represents one of the most common reaction for the synthesis of quinoline core for more than a century, its mechanism is still dedebated. To date, both of the two more popular mechanistic explanations are involving fragmentation-recombination pathways. In the first one, initially the amine reacts with the aldehyde or ketone under acidic conditions to form an imine. Dimerization and Pictet-Spengler type cyclization forms a diazetine core. Protonation and subsequent cyclization-ring cleavage reaction assembles the isoquinoline nucleus. 

In 1988, Zhang et al. ° achieved the synthesis of the optically active tetracyclic ketone 160, in a stereospecific fashion by employing the asymmetric Pictet—Spengler reaction. Many improvements have been made to prepare both the Na-H and the Na-Me tetracyclic ketones (158 and 160, respectively). The Pictet—Spengler reaction is now carried out in one pot to provide only the desired iraws-diastereomer with high diaster-eoselectivity and enantioselectivity. As illustrated in Scheme 2, after Nb-benzylation of d-(+)-tryptophan methyl ester (156) with benzaldehyde and sodium borohydride in methanol, trifluoroacetic acid (TFA) was added to the reaction vessel at 0 °C to neutralize the reaction mixture. After removal of the solvent, CH2CI2, TFA, and methyl 4,4-dimethoxybutyrate... 

---